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Original Studies |
Diabetes and Endocrine Research Laboratory (H.L., E.L., P.A., Å.G., L.G., T.T.), Department of Endocrinology, Lund University, S-20502 Malmö, Sweden; and Department of Internal Medicine (C.F., T.T.), Helsinki University Central Hospital, FIN-00029 Helsinki, Finland
Address all correspondence and requests for reprints to: Dr. Tiinamaija Tuomi, Wallenberg Laboratory, Department of Endocrinology, Lund University, S-20502 Malmö, Sweden.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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We conclude that type 1 and type 2 diabetes cluster in the same families. A shared genetic background with a patient with type 1 diabetes predisposes type 2 diabetic patients both to autoantibody positivity and, irrespective of antibody positivity, to impaired insulin secretion. The findings support a possible genetic interaction between type 1 and type 2 diabetes mediated by the HLA locus.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The consequence of such genetic admixture for type 2 diabetes is not known. In populations of European origin, 10% of patients diagnosed with type 2 diabetes have antibodies to glutamic acid decarboxylase (GADab), which is associated with subsequent development of insulin deficiency (11, 12, 13, 14, 15). However, the interaction between type 1 and type 2 diabetes may not be restricted to GADab-positive patients. In populations with a high prevalence of type 1 diabetes, a large proportion of patients with type 2 diabetes should have inherited susceptibility genes for both types of diabetes. Thus, type 1 diabetes susceptibility genes could contribute to the polygenic etiology of type 2 diabetes and modify its clinical manifestation. Indeed, a family history of type 1 diabetes was associated with lower fasting C-peptide concentration and a lower frequency of cardiovascular disease in patients with type 2 diabetes (16). Some studies have reported an increased frequency of human leukocyte antigen (HLA)-DR4 or HLA-DR3/DR4 (17, 18, 19, 20) in patients with type 2 diabetes, but this increase was mainly restricted to patients with relative insulin deficiency or islet cell antibodies (ICA) and/or GAD (15, 17, 20). In addition, excess transmission of DR4-linked haplotypes, from parents with type 2 diabetes to offspring with type 1 diabetes, has been reported (21). Taken together, these data point to a genetic interaction between type 1 and type 2 diabetes that could be mediated by the HLA locus.
To further elucidate this interaction, we investigated, in families with both type 1 and type 2 diabetes, whether family history of type 1 diabetes and/or sharing a risk HLA haplotype with a member with type 1 diabetes influenced the manifestation of type 2 diabetes.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The Botnia study is a population-based study aiming at the identification of genes that increase susceptibility to type 2 diabetes (22). Since 1990, we have recruited 850 families with at least 1 member with type 2 diabetes, from Finland (16). Of them, 695 (82%) had more than 1 type 2 diabetic patient and were included in the present study. The mean family size was 8, including (on average) 2.4 type 2 diabetic patients per family (n = 1658). All available family members were invited to participate in the study, and an oral glucose tolerance test (OGTT) was performed on more than 90% of the subjects studied. Diabetes was diagnosed according to the new World Health Organization criteria (23). Diagnosis of type 1 diabetes was based on initiation of insulin treatment within 6 months after diagnosis and/or fasting C-peptide concentrations less than 0.2 nmol/L. Patients who did not fulfill these criteria were considered to have type 2 diabetes. However, all type 2 diabetic patients in the present study had been treated with diet and/or oral hypoglycemic agents for at least 1 yr before commencing insulin treatment. Informed consent was obtained from all subjects, and the study was approved by the local ethics committee. Families with genetically confirmed maturity-onset diabetes of the young (MODY1, MODY2, MODY3) (24) were excluded. Families with only type 2 diabetes were called common type 2 families. Families in which type 1 diabetes occurred among the first-, second-, or third-degree relatives of type 2 diabetic patients were called mixed type 1/2 families. GADab were analyzed in 1451 of the 1658 (88%) patients diagnosed with type 2 diabetes.
Study design
To compare the HLA-DQB1 genotype frequencies, we randomly selected one patient from each mixed type 1/2 family (n = 93) and compared them with randomly selected patients from 195 common type 2 families. In addition, we compared the genotype frequencies with those of: 1) 172 GADab-negative control subjects from the Botnia study [nondiabetic spouses, 77 males (M)/95 females (F); mean age, 57.1 ± 12.9 yr]; and 2) 126 patients with adult-onset type 1 diabetes from the Diabetes 2000 Registry in Southern Sweden (73 M/53 F; age at diagnosis, >20 yr; mean, 30.7 ± 8.6 yr). These adult-onset type 1 diabetic patients were of similar age, at diagnosis of diabetes, and had a similar frequency of DQB1 genotypes as those Finnish adult-onset type 1 diabetic patients participating in the Botnia study (n = 32) (15).
Among the mixed type 1/2 families, we compared the glucose and insulin responses during OGTT between family members who had (HLA+) or did not have (HLA-) a type 1 diabetes susceptibility HLA haplotype (either DR3(17)-DQA110501-DQB1102 or DR410401/4-DQA110301-DQB110302) (25, 26). We studied 36 families with, on average, 9 members (range, 4–40). The comparisons were restricted to those family members not treated with insulin who would share, at most, 25% of the chromosomes, i.e. second-degree or more distant relatives of the type 1 diabetic patients. These included 68 type 2 diabetic (42 HLA+ and 26 HLA-) and 122 nondiabetic (75 HLA+ and 47 HLA-) relatives.
To test whether differences in glucose and insulin responses between the HLA+ and HLA- family members were attributable to the presence of susceptibility class II HLA DRB1-DQB1 haplotypes per se or whether actual sharing of the chromosomal region with a patient with type 1 diabetes was needed, we established HLA-sharing identity by descent (IBD) by following the haplotype of the type 1 diabetic proband in the families. In families with more than one patient with type 1 diabetes, the patient diagnosed first was regarded as the type 1 proband, whose HLA haplotypes were followed. Among the 36 families included, 27 (64%) diabetic and 33 (44%) nondiabetic HLA+ subjects shared the class II haplotype IBD (HLA-IBD+) with the type 1 proband of the family.
As with the mixed type 1/2 family members, we also compared the glucose and insulin response to OGTT, according to the presence of risk DRB1-DQB1 haplotypes, in a group of unrelated GADab-negative (122 diabetic and 158 nondiabetic) subjects without a family history of type 1 diabetes. Subjects with one risk and one protective (DR2115-DQB110602/3) haplotype were excluded from the analysis.
HLA genotyping
The second exon of the HLA DQA1 and DQB1 genes was amplified by PCR, followed by dot-blot hybridization with sequence-specific oligonucleotide probes labeled with digoxigenin (DIG Oligonucleotide 3'-End Labeling Kit, Roche Molecular Biochemicals, Mannheim, Germany) (15). Nine DQB1 probes were used to distinguish DQB1 alleles 0201 or 0202 (02), 0301, 0302, 0303, 0501, and either 0602 or 0603 (0602/3), and 0401 or 0402 (0401/2). Ten DQA1 probes were used to distinguish DQA1 alleles 0101, 0102, 0103, 0301, 0302, 0201, 0501, and either 0401 or 0601 (0401/0601). The probe sequences originated from the 11th International Histocompatibility Workshop (27).
HLA DRB1 was typed by a group-specific PCR, employing seven primer-pairs to amplify DR1, DR2, DR3/5/6/8, DR4, DR7, DR9, and DR10 (28). Using restriction fragment length polymorphism analysis, the DR1 group was further subdivided into DRB110101, 10102, and 10103 alleles; the DR2 group into DR2(15) and DR2(16) alleles; and the DR3/5/6/8 group into DR3(17) and DR3(18), DR5(11) and DR5(12), DR6(13) and DR6(14), and DRB110801/3 and DRB110802/4 alleles. The DR4 group was similarly divided into six subgroups: DRB110401/4/8 (10401, 10404, or 10408); DRB110402; DRB110403/7 (10403 or 10407); DRB110405/9/10 (10405, 10409, or 10410); DRB110406; and DRB110411. A further subtyping for the DR4 subgroups was performed by dot-blotting to identify the 10403 and 10401/4 alleles (29).
In pedigrees where IBD segregation of the class II HLA-haplotypes could not unambiguously be deduced, we typed three additional microsatellite markers (D6S291, D6S1691, and D6S299) located 5 cM centromeric, 3 cM telomeric, and 5 cM telomeric to the HLA class II locus, respectively (data not shown). The primer sequences, allele sizes, and genetic marker order were obtained from the Genome Database. The markers were typed by fluorescence-based PCR (30). The extended HLA haplotypes were constructed both manually and with the GENEHUNTER linkage program (31).
Metabolic measurements
An OGTT was performed for all subjects more than 15 yr old, with fasting blood glucose less than 10 mmol/L, and not treated with insulin. After 12 h of overnight fast, the subjects ingested 75 g glucose in a vol of 300 mL. Samples for measurements of blood glucose and serum insulin were drawn at -10, 0, 30, 60, and 120 min; and incremental glucose or insulin areas under the curve were calculated. Blood glucose was measured with a hexokinase method with a coefficient of variation (CV) less than 1% (Roche Molecular Biochemicals). Serum insulin concentrations were measured by RIA (Pharmacia Biotech, Uppsala, Sweden) with an interassay CV of 5%. Fasting serum-C-peptide concentrations were measured in duplicate by an RIA with an interassay CV of 9% (Human C-peptide RIA Kit, Linco Research, Inc., St. Charles, MO). Hemoglobin A1c (HbA1c) concentration was measured by a high-pressure liquid chromatography with a reference range of 5–7%. GADab were measured by a radioimmunoprecipitation method employing 35S-labeled recombinant human GAD65 produced by in vitro transcription/translation (15).
Statistical analysis
Data are presented as mean ± SD for normally
distributed variables, as median (interquartile range) for nonnormally
distributed variables, and as percentages for categorical variables.
The statistical analysis was performed with either Biomedical Data
Processing (BMDP; Los Angeles, CA) or Number Cruncher Statistical
Systems (NCSS; Kaysville, UT) statistical software. The group
frequencies were compared using the 
-squared or Fisher’s exact
tests, and group means using the Mann-Whitney or the Kruskall-Wallis
tests.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Among 695 families, ascertained through the presence of more than 1 patient with type 2 diabetes, patients with type 1 diabetes were observed in 100 families (14%). Of them, 30% had more than one member with type 1 diabetes. Thirty-seven (5.3%) of 695 randomly selected probands with type 2 diabetes had a first-degree relative with type 1 diabetes.
Compared with patients from families with only type 2 diabetes, the
type 2 diabetic patients from the mixed type 1/2 families had a lower
body mass index (BMI) (P = 0.004) and lower fasting
C-peptide concentrations (P = 0.031) (Table 1
). They were also more often treated
with insulin (all patients: 42% vs. 32%; P
= 0.003; GADab+ patients: 55% vs. 59%, P =
NS; GADab- patients: 38% vs. 30%, P =
0.050). However, when compared with the adult-onset type 1 diabetic
patients, the mixed patients were older at diagnosis (P
< 0.0001) and had higher BMI (P < 0.0001) and higher
fasting C-peptide concentrations (P < 0.0001) (Table 1).
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GADab were found more often in type 2 diabetic patients from the
mixed type 1/2 families (18%) than in those from the common type 2
families (8%, P < 0.0001) (Table 1
). Forty-two of the
139 (30%) GADab-positive patients with type 2 diabetes had a family
history of type 1 diabetes, compared with 198 of 1312 GADab-negative
patients (15%) (P < 0.0001). Of the 126 patients with
adult onset type 1 diabetes, 82 (65%) had GADab after a median
diabetes duration of 17.5 (18.2) yr.
The frequency of GADab among the nondiabetic relatives was not significantly different from the frequency in the general population (4.4%, 17 of 383), either in the mixed type 1/2 (4.3%, 13 of 297) or in the common type 2 diabetes (3.1%, 28 of 905) families.
Figure 1 shows the DQB1 genotype
frequencies stratified according to GADab positivity and family history
of diabetes. The type 2 diabetic patients from the mixed 1/2 families
had, nearly as often, the 0302/X genotype conferring an increased risk
for type 1 diabetes (25%) as the adult-onset type 1 diabetic patients
(32%). The frequency was twice as high as that seen in patients from
the common type 2 families (12%, P = 0.005) or in the
nondiabetic control subjects (12%, P = 0.008). Of
note, although the GADab+ patients, in general, had an increased
frequency of the 0302/X genotype, it was higher in both GADab+ and
GADab- patients from mixed, compared with those from the common type 2
families (Fig. 1). On the contrary, the frequency of the 02/0302
genotype conferring the highest risk for type 1 diabetes did not differ
among the patients from mixed families (4%), common type 2 families
(3%), or the nondiabetic control subjects (4%), whereas it was
significantly lower in all these groups, compared with the adult-onset
type 1 patients (27%, P < 0.001) (Fig. 1).
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). The genotype frequencies of the nondiabetic relatives from the mixed type 1/2 families were 6% for 02/0302, 17% for 0302/X, 23% for 0201/X, and 17% for 0602(3)/X. Thus, they did not significantly differ from the type 2 diabetic patients from the same families (4%, 25%, 25%, and 16%, respectively).
HLA risk-haplotypes and insulin response among subjects from mixed type 1/2 families
Diabetic relatives. Despite similar age and BMI, the fasting
glucose concentration (P = 0.005) and the incremental
glucose area during OGTT (P = 0.004) were significantly
higher in diabetic HLA+ patients than in their diabetic HLA- relatives
(Table 2). In addition, insulin response
during OGTT [insulin area: 3666 (3514) vs. 7024 (5437),
P = 0.044] and the ratio of insulin to glucose area
[5.9 (11.3) vs. 15.2 (17.9), P = 0.005]
were significantly lower in the HLA+ patients than in the HLA-
patients. These differences were unaltered when only GADab- patients
were considered [Fig. 2, glucose area:
601 (343) vs. 393 (241) mmol/L; P = 0.004;
insulin area: 3706 (3803) vs. 7291 (5692) mU/L,
P = 0.016. The ratio of insulin to glucose area: 6.1
(12.5) vs. 17.6 (17.2), P = 0.002].
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We also analyzed the subjects according to whether they actually shared
the HLA risk haplotype with their type 1 diabetic relative. When only
the patients sharing HLA haplotypes IBD with the type 1 diabetic
proband were included, the difference in glucose area [682 (286)
vs. 442 (306) mmol/L; P = 0.002], as well
as the ratio of insulin to glucose area [4.8 (4.7) vs. 12.5
(15.3)] and the early-phase insulin secretion [30-min insulin area,
320 (278) vs. 572 (594) mU/L, P = 0.015]
were maintained between the HLA-IBD+ (n = 27) and HLA-IBD-
(n = 41) groups. Again, the differences in glucose and insulin
responses were not attributable to the presence of GADab [GADab-,
glucose area: 682 (324) vs. 433 (300) mmol/L,
P = 0.004; 30-min insulin area: 321 (191)
vs. 620 (696) mU/L, P = 0.041; the ratio of
insulin to glucose area: 5.9 (3.5) vs. 14.0 (15.2),
P = 0.020; see Fig. 4].
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). However, when only the 33 (44%)
nondiabetic subjects sharing HLA haplotypes IBD with the type 1
diabetic proband were considered, they had greater glucose area [249
(261) vs. 172 (161) mmol/L, P = 0.003] and
lower incremental insulin-to-glucose ratio at 30 min [6.6 (5.5)
vs. 9.8 (8.6) mU/mmol, P = 0.017] or 2
h [12.4 (9.5) vs. 17.5 (13.9), P = 0.007]
than the 89 HLA-IBD- subjects. Once again, these differences did not
change when the GADab+ subjects were excluded (Figs. 3 and 4).
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To further test whether high-risk HLA haplotypes predisposing to type 1 diabetes per se explained the above findings or whether actual sharing of the chromosome IBD with the type 1 diabetic relative was essential, we also studied GADab-negative unrelated type 2 diabetic (n = 122) and nondiabetic (n = 158) subjects without a family history of type 1 diabetes. We compared the insulin and glucose responses during OGTT between those with (HLA+)- and without (HLA-)-risk HLA haplotypes (see Subjects and Methods). The proportion of HLA+ class II haplotypes between the diabetic and nondiabetic subjects was similar (34% vs. 34%).
Different from the relatives in the mixed type 1/2 families (see
above), there was no difference between the HLA+ (n = 41) and the
HLA- (n = 81) diabetic subjects, with respect to either glucose
[548 (294) vs. 573 (224) mmol/L x 2 h] or insulin
[4243 (6029) vs. 4604 (5711) mU/L x 2 h] areas
during OGTT (Table 3 and Fig. 4).
Similarly, among the nondiabetic subjects, no difference was observed
between the HLA+ (n = 53) and the HLA- (n = 105) nondiabetic
subjects, with respect to insulin [4397 (3985) vs. 4519
(4104) mU/L x 2 h] and glucose [204 (206) vs. 204
(148) mmol/L x 2 h] areas during OGTT (Table 3 and Fig. 4).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The data further support the view that a shared genetic background with a type 1 diabetic family member influences the phenotype of the type 2 diabetic patient, i.e. they were less obese, had earlier onset of diabetes and lower C-peptide concentrations, and were more often treated with insulin than type 2 diabetic patients without such family history. As reported earlier, GADab positivity was also more common in mixed, than in common type 2, patients (17.5% vs. 8%; P < 0.0001) (16). The prevalence of GADab (9%) in the whole type 2 diabetes population is in accordance with figures reported from other countries (14, 35).
The type 2 diabetic patients from the mixed type 1/2 families shared an increase in the moderate-risk HLA-DQB110302/X genotype (36) with the adult-onset patients with type 1 diabetes. Because they were relatives of type 1 diabetic patients, this was per se not unexpected. However, similar sharing of the genotype conferring the highest risk, 02/0302, or absence of the genotype conferring protection, 0602(3)/X, was not observed except for the GADab-positive subgroup of patients from the mixed type 1/2 families. It is of interest that, if we compare GADab-positive patients from mixed type 1/2 families and the common type 2 families, only the patients from mixed families share the 02/0302 and 0602(3) association with type 1 diabetic patients, whereas all GADab-positive patients share the 0302/X association. This finding suggests that part of the observed heterogeneity among the GADab-positive type 2 diabetic patients (i.e. patients with latent autoimmune diabetes) (11, 13, 14, 15) could be ascribed to type 1 family history.
The high frequency of GADab in mixed patients could reflect autoimmune insulitis, and one could argue that the differences were attributable to misclassification of the patients, i.e. adult-onset type 1 diabetes masquerading as type 2 diabetes. Because of the cross-sectional nature of the study, we cannot totally refute that interpretation, but we consider it unlikely for the following reasons. An increase in the 0302/X genotype frequency was seen also in the GADab-negative patients from the mixed type 1/2 families, and sharing of class II HLA risk haplotypes with a family member with type 1 diabetes was associated with a reduced insulin response to OGTT independent of the presence of GADab. Also, all type 2 diabetic patients were noninsulin-treated for at least 1 yr after diagnosis. On the other hand, a considerable proportion of the patients would fulfill the criteria for latent autoimmune diabetes in adults. It is possible that some of the patients diagnosed with type 2 diabetes in the mixed type 1/2 families could have been positive for GADab or other autoantibodies at onset but not at the time of testing. However, all available data for GADab show that they are stable over the years (37, 38, 39, 40). As to the other antibodies, no data exist on patients with newly-diagnosed adult-onset type 1 diabetes at the age of over 40 yr, which would be the relevant age-group for our study. In the study by Gorus et al., 85–88% of patients between 20 and 40 yr at diagnosis were positive for GADab, which represented 92–95% of those positive for any diabetes-associated autoantibody (41); 1.4% were positive for IA2-ab, and 4% for ICA, though negative for GADab. In addition, 12% of Swedish patients who were 15–34 yr old at diagnosis of diabetes of unclear type had ICA in the absence of GADab (42). However, among patients clinically diagnosed with type 2 diabetes, as our patients were, only 1.6–2.3% of the 1538 UKPDS patients who were 25–65 yr old at diagnosis were ICA+ in the absence of GADab. Accordingly, our cross-sectional data on the Botnia Study showed 0.5% of 517 GADab- type 2 diabetic patients to have IA2-ab and 0.6% to have ICA (15). In addition, IA2ab were analyzed in 75% of the GADab- relatives included in the analysis of insulin response to OGTT, and none of them had IA2ab (data not shown). Thus, we do not think that the results can be explained by misclassification of patients.
Could it be that 0201/0302 is associated with a more aggressive insulitis (and thus, susceptibility to type 1 diabetes), whereas 0302/X confers risk to both types of diabetes, e.g. through subclinical insulitis? An increase in HLA-DR4, which is in linkage-disequilibrium with the DQB110302 allele and in type 1 diabetes-associated HLA-haplotypes, has previously been reported in patients with type 2 diabetes (18, 19, 21, 43). More recently, it was shown that type 2 patients with DR4 had a lower cardiovascular mortality rate than that of DR4 negative patients (44). This is compatible with our data on lower BMI, lower C-peptide concentrations, and lower frequency of coronary artery disease in mixed patients compared with common type 2 patients (16), because both obesity and insulin resistance are considered risk factors for cardiovascular disease (45).
The nature of such an autoimmune process remains obscure but could involve two possibilities. A genetically determined autoimmune attack could have reduced the pancreatic ß-cell capacity of the HLA-sharing relatives early in life. Only histological analysis of the pancreatic islets could confirm this. Another possible explanation is that the HLA-sharing relatives are in the process of developing type 1 diabetes or have subclinical autoimmune insulitis reducing their ß-cell capacity. It is well established that 6–10% of first-degree relatives of patients with type 1 diabetes develop type 1 diabetes (1, 46, 47, 48, 49). First-degree relatives with ICA (26, 48, 50, 51) or relatives of young probands (21, 52) seem to have a higher risk of developing type 1 diabetes, but the effect of probands age is controversial (47). For siblings, HLA-identity with the proband is associated with a 10–30% risk, and HLA-haploidentity with a 4–9% risk, of developing type 1 diabetes, whereas the risk for HLA-nonidentical siblings does not differ from that for the general population (26, 48, 53, 54). It is not known what the risk of developing type 1 diabetes is for more distant relatives who are haploidentical for the HLA-type. However, based on the risk estimates for the first-degree relatives, it is unlikely that a major proportion of the second-degree or more distant relatives that we have been studying would develop type 1 diabetes.
In contrast to the findings in family members, type 2 diabetic patients
without type 1 family history who had high- or moderate-risk class II
HLA alleles did not demonstrate any deterioration of glucose tolerance
or impairment in insulin secretion. The same applied for the
nondiabetic relatives of type 1 diabetic subjects, unless they shared
the HLA haplotypes IBD with the type 1 diabetic relative. This would
suggest that some other gene than the HLA-DQB1 (or combination of
alleles) in this region is required to manifest the metabolic effects.
The current study was not designed to identify these genetic factors,
but there are several candidates. Although the class II HLA locus
accounts for most of the increased susceptibility to type 1 diabetes
(
s = 3.1), at least 15 other chromosomal loci have been shown
to increase susceptibility to type 1 diabetes. Some of them are located
near the HLA region on the short arm of chromosome 6 (55, 56). Linkage disequilibrium mapping, using a dense SNP map of
the region in the mixed families, could provide some clues to the
nature of these genetic factors.
We conclude that genetic susceptibility to type 1 diabetes conferred by the HLA locus predisposes to impaired ß-cell function in patients with type 2 diabetes. The findings have important clinical implications by emphasizing the profound effect of a family history of type 1 diabetes on the phenotype of patients with type 2 diabetes. Further studies are required to precisely define the alleles or combination of alleles increasing susceptibility to impaired ß-cell function in patients with type 2 diabetes.
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Acknowledgments |
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Footnotes |
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Received April 19, 2000.
Revised October 6, 2000.
Accepted October 16, 2000.
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, GADab+ subjects; 
, GADab- subjects.
, HLA-, n =
23, dashed line) a risk HLA-haplotype.
P = 0.004 for the difference in glucose area and
P = 0.016 for insulin area between HLA+ and HLA-
patients.
